The present invention relates to the fields of x-ray therapy and x-ray surgery. More specifically, devices and enhanced methods for performing such therapeutic techniques, comprising the use of pharmaceutical contrast agents, are provided.
Since early in the twentieth century it has been recognized that the ionizing properties of x-rays allow them to be used for therapeutic and diagnostic purposes. However, treatment of tumors with x-rays is difficult because about the same x-ray dose is required to kill the cancerous cells as kills healthy cells. Therefore, techniques for concentrating the x-ray dose in the target area, with minimum dose to surrounding healthy tissue, are of basic importance in radiotherapy and radiosurgery.
An example of radiotherapy is illustrated in FIG. 1. Radiotherapy consists of bathing large volumes of the body 10 in direct radiation 20 generated from a conventional therapy x-ray source 30. Usually performed at 1 MeV or more, the goal is to damage both healthy and diseased cells. The healthy cells are better able to repair the damage and remain viable while the diseased cells die.
In recent years, photons with energy in excess of 1 MeV have been preferred for therapeutic purposes over the more traditional medical x-rays in the 50 to 100 keV band. This is because of several factors. First, the beam intensity drops less quickly as it passes through the body, yielding a more uniform dose at the target site. Second, the primary photoelectrons (which cause tissue damage) are created by Compton scattering of the high-energy photons and penetrate inward from the site of the interaction. This leads to low dose deposition at the skin, and a buildup effect inward. Third, because the beam absorption is dependent only on the density of the tissue, and not upon the composition, there is little interaction with bones.
In the last fifteen years, as computed tomography (CT) and magnetic resonance imaging (MRI) have improved imaging of the body, a new technique, known as radiosurgery, has been developed. Radiosurgery is illustrated in FIG. 2. Radiosurgery targets a specific part of the body, such as the head 12. By moving the x-ray source 30 through an arc as shown by the arrows 40, with the isocenter at the hub of the arc 40, the diseased tissue is given a higher dose than the healthy tissue. To achieve a lethal x-ray dose deep inside the body, the x-ray beam is brought to bear on the target tumor from a variety of directions, spreading the beam across as much healthy tissue as possible, but always remaining aimed at the target. This is done by creating dozens of narrow beams from radioactive decay (as in the case of the gamma knife) or by scanning an x-ray source across a series of arcs in the case of a linear accelerator (LINAC). Both techniques are effective and in general practice. However, even with these radiosurgical techniques, collateral damage to nearby tissue remains a major problem because the x-ray beams spread to the side and overshoot the target.
Contrast agents are currently used to enhance the x-ray visibility of soft tissue structures. The higher cross section that the heavy elements present to the x-rays used in medical applications allows this technique to be successful. This x-ray dose enhancement caused by the contrast agents has been viewed as a detrimental side effect of diagnostic imaging in the past because it causes cellular, particularly DNA, damage. Such concerns are discussed in the literature, mostly relating to angiography or excretory urography, two procedures that deliver exceptionally high diagnostic doses to the patient, as discussed by Callisen et al., Cochran et al., and Weber et al.
From concerns related to cell damage caused by the use of high doses of contrast agents came the idea that the damaging effects on cells could be used to improve radiotherapy. Several papers have discussed the use of contrast agents to enhance the effect of x-rays for tumor treatment and have demonstrated that enhancement works in several model systems. Hadnagy et al. showed that contrast agent alone or contrast agent combined with x-rays increased radiation-induced chromosomal aberrations in blood cells. The amount of aberration was dependent on iodine concentration. Fairchild et al. relates to theoretical considerations of the use of iodinated deoxyuridine as an enhancing agent for treating tumors. Santos Mello et al. refers to considerations and results relating to the therapeutic advantages of loading tumors in mice, particularly brain tumors, with iodine and treating them with low-energy photons. They achieved a dose enhancement of up to 3 in lymphocytes. Iwamoto et al. relates to use of low-energy x-rays and iodine to treat brain tumors in rabbits. They found a dose enhancement of about 30% by using the combination. Dawson et al. relates to treating cells in vitro with various concentrations of iodine. They found radiation enhancement of cell damage with an iodine concentration of 50 mg/ml. Cochran and Norman relates to findings of chromosome damage in patients subjected to nonionic contrast media. Iwamoto et al. (see also U.S. Pat. No. 5,008,907) discusses the use of a CT scanner and collimator, together with contrast agent, to treat brain tumors. In this report, the dose enhancement was determined to be about 50%. Cohen et al. relates to use of Gd-DTPA contrast agent to detect changes in microvascular characteristics in rats implanted with a tumor. Norman et al. relates to use of iodinated contrast agent together with x-rays for treating brain tumors. They also suggest using gadolinium as a contrast agent.
None of these references proposes a device specifically designed to make maximum use of the contrast agent to enhance x-ray therapy or x-ray surgery or specific methods therefor.
None of these references discusses methods to precisely calibrate the amount of contrast agent desired in a tumor nor methods to accurately deliver the amount of contrast agent necessary to produce a radiation dose enhancement of greater than 2:1 in the tumor over the normal tissues. None of these references discusses methods of treating only the surface of the tumor to destroy the tumor vasculature and also maintain a safe dose of radiation to the normal tissues.
We have discovered that increased enhancement in the local x-ray dose to a target tumor can be created with the correct combination of x-rays and contrast agents. Contrast agents which comprise a heavy element, for example, iodine, gadolinium, or gold, are introduced into the patient either by direct injection or intravenously.
A typical contrast agent comprises a compound that contains a large percentage of a heavy element from the upper half of the periodic table, such as iodine, gadolinium, or gold. For x-ray diagnostics, the most common heavy element used is iodine. At diagnostic energies, typically about 18 to about 80 keV, the absorption cross section of iodine is much higher than that of the elements that form most human tissue. Thus, even in relatively small amounts, iodine can add significantly to the absorption of x-ray radiation.
A preferred method of the present invention for treatment of a tumor (or other target) comprises the following steps. First, the tumor is visualized by ultrasonography or computed tomography (CT), and contrast agent is delivered into the tumor, or into a surface portion of the tumor, preferably by intravenous or direct injection. Second, the amount of contrast agent in the tumor is calibrated. Third, the first two steps are iterated until a desired amount of contrast agent is achieved as uniformly as possible throughout the tumor or in the surface portion only of the tumor, in order to provide a desired amount of x-ray dose enhancement. Fourth, the tumor is irradiated by a low-energy, orthovoltage x-ray source before the contrast agent leaks from the tumor. We have discovered that with proper calibration as described herein, in most cases the tumor will show a strong to complete response within four weeks. Adjacent body tissues are completely unharmed.
In another preferred embodiment, the method for injecting the tumor includes the deliberate injection of only a surface portion of the tumor in cases where the tumor mass is too large to be filled in toto. Injection of the surface portion of large tumors permits delivery of higher doses of radiation to this area of the tumor than is possible with conventional or previously described techniques. It is believed that this method destroys the blood supply to the tumor and its growing periphery only. Therefore, we kill the cancer more efficiently than by conventional techniques that deliver a higher radiation dose to the center of the mass.
Although many tumors are small enough and soft enough to inject directly with contrast agents, we have found that this method will not work well for large or hard tumors. In the case of a tumor that is too big or too fibrotic to fully inject with enough contrast agent, the above-noted technique involving injection of the surface portion is used for treatment. Only the outer regions of the mass are injected and subsequently irradiated. The entire periphery or corona of the tumor is injected. These injections can be directed visually or by ultrasonography or CT. The depth of the injection may include up to about 20% to about 30% of the radius of the tumor. For example, in a tumor having a radius of 2 cm, the injected surface portion would extend up to 0.5 cm deep as measured from the circumference. After injection, the amount of the contrast agent is calibrated. The subsequent deposition of high doses of radiation to the entire sphere of tissue surrounding the tumor encases sit in a shell lacking any vascular support.
In another embodiment of the present invention, contrast agent is intravenously injected. The contrast agent then spreads through the vascular system and, under normal conditions, is generally confined to that route. However, at the site of a tumor the vasculature is leaky. This allows the contrast agent to spread into the tissue of the tumor, where it accumulates to higher concentrations than in surrounding tissue. The amount of contrast agent in these regions of accumulation within the tumor is calibrated using diagnostic equipment. The percentage of iodine achieved in the tumor is often too low to achieve a sufficient therapeutic amount for a complete response, but when focused beams are used, highly advantageous results are achieved. Another use of intravenous delivery is when the blood vessels themselves are targeted (e.g., vascular malformations or pathology), since the therapeutic ratio of contrast agent in the blood can be very high, killing blood vessels, but not tissue.
Injections of tumors within the body are performed under the guidance of ultrasonography or CT visualization. Injections via ultrasound are performed in real-time and involve multiple needle placements to cover the volume. The needles are arranged to cover the lesion in a fashion that is analogous to the placement of sources for brachytherapy. However, once the injections are completed the needles are removed. Injections under CT guidance are similar, but the operator leaves the room between injections so as not to be exposed to radiation. Following the definition of the volume to be treated with the above methods, the amount of contrast agent is calibrated and the injections are repeated until high concentration is achieved. The amount of the contrast agent is calibrated from the digital output of orthogonal fluoroscopic or CT views of the lesions post-injection. We have discovered that by using such contrast agents, preferably with optically focused x-rays, for example, those produced according to U.S. Pat. No. 5,604,782, or various other methods of focusing x-rays as are known in the art, the therapeutic ability of the x-rays, particularly for treating tumors, is greatly enhanced.
Thus, the present invention comprises a method for treating tumors by pharmaceutically enhanced radiosurgery with focused x-rays beams that includes the steps of injecting a contrast agent either intravenously into the patient or directly into the tumor and then calibrating the amount of contrast agent within the tumor in order to determine the x-ray dose enhancement that exists in the tumor compared with the surrounding tissue, which contains less or no contrast agent. The calibration of the amount of contrast agent within the tumor is performed by using at least two equations. The first equation measures x-ray dose enhancement de on the basis of the weight percent p of contrast agent within the tumor, that is, by de=1+1.3p. The second equation measures x-ray dose enhancement de on the basis of the Hounsfield number H for the contrast agent, that is, by de=1+0.0025H. The Hounsfield number H is determined by placing the contrast agent-injected tumor in a CT scanner and measuring the Hounsfield number H directly off the display screen of the scanner. The injection of the contrast agent and the calibration of the amount of contrast agent to determine x-ray dose enhancement in the tumor are repeated until the desired amount of dose enhancement is achieved, from about 2:1 to about 10:1 compared with the dose in normal tissue. The tumor is then irradiated with a focused x-ray beam having an energy level of about 40 keV to about 80 keV. The x-ray beam is focused by a mirror array as described hereinbelow.
These and other advantages, features, and objects of the present invention will be more readily understood in view of the following detailed description and the drawings.